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J. Biol. Chem., Vol. 279, Issue 47, 48883-48892, November 19, 2004

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Identification of an Evolutionarily Conserved Domain in Human Lens Epithelium-derived Growth Factor/Transcriptional Co-activator p75 (LEDGF/p75) That Binds HIV-1 Integrase^*

Peter Cherepanov, Eric Devroe¶||, Pamela A. Silver¶||, and Alan Engelman**

From the Departments of Cancer Immunology and AIDS and ^¶Cancer Biology, Dana-Farber Cancer Institute and the Departments of Pathology and ^||Systems Biology, Harvard Medical School, Boston, Massachusetts 02115

Human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) protein was recently identified as a binding partner for HIV-1 integrase (IN) in human cells. In this work, we used biochemical and bioinformatic approaches to define the domain organization of LEDGF/p75. Using limited proteolysis and deletion mutagenesis we show that the protein contains a pair of evolutionarily conserved domains, assuming about 35% of its sequence. Whereas the N-terminal PWWP domain had been recognized previously, the second domain is novel. It is comprised of 80 amino acid residues and is both necessary and sufficient for binding to HIV-1 IN. Strikingly, the integrase binding domain (IBD) is not unique to LEDGF/p75, as a second human protein, hepatoma-derived growth factor-related protein 2 (HRP2), contains a homologous sequence. LEDGF/p75 and HRP2 IBDs avidly bound HIV-1 IN in an in vitro GST pull-down assay and each full-length protein potently stimulated HIV-1 IN activity in vitro. LEDGF/p75 and HRP2 are predicted to share a similar domain organization and have an evident evolutionary and likely functional relationship.

Received for publication, June 7, 2004 , and in revised form, August 24, 2004.

^* This work was supported by an HHMI Predoctoral Fellowship (to E. D.), the Claudia Adams Barr Fund (to P. A. S.), and National Institutes of Health Grant AI39394 (to A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Materials.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY728140, AY728141, and AY728142.

^** To whom correspondence should be addressed: Dept. of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel.: 617-632-4361; Fax: 617-632-3113; E-mail: alan_engelman{at}dfci.harvard.edu.

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